Method of making 2-amino-5-substituted-1,3,4-thiadiazole



Patented Feb. 14, 195Q METHOD OF .MAKING Z-AMINO-S-vSUBSTI- TUTED-LiZA-THIADIAZOLE George W. Steahly, St. Louis, "-Mo., assignor to .Monsanto Chemical Company, St. Louis, Mo., a corporation of Delaware.

"No Drawing. Application June 28, 1946,

Serial No. 680,077

19- Claims.

!rhisdnventiomrelates ito z1-, 3;4thiadiazoles..and

imore :particu'larly 'to an improved .method of 1 making l2-amino-5esubstituted-1,3 ,4-thiadiazo1es.

3'2-- Amino- 5- -usubstituted'- 1,3,4 .thiadiazoles are generally .prepared .-by zcondensing an lacyl :lBhIOIidl-E with an excess of :thiosemicarbazide. Ihe 1,-yields lby this proc'ess are relatively 110w, .ranging itrom :approximately 30% to approxi- Smately 145% Certain 2+amino-1,3;4 thiadiazoles ihaving ia substituentzin the .5-position, for ex- :ample, :alkyl, falkenyl, aralkyl and cycloalkyl radicals have been found useful as "analgesic agents. Certain of the 2-sulfani1yl derivatives of 2 amino -'5 substituted 1,3,4 thia diazoles, for example the 5-alky1 and 5- alkenyl derivatives having fromfl to *4 'carbonatoms in the alkyl "-and alkenylradicals and vthe z5-cycloalkyl= derivatives, have been found to be striking- -ly active as anti-bacterial agents. The low .yields obtained by the usual process of precparing the .tniadiazoles renders the manufacturing cost of these compounds relatively :high and it is most. desirable that .a method be found which will reduce the manufacturingcost by providing better yields of the desired compounds.

:According to the-method ofithe presentinvention, generally stated, substantially improved ,yields-of -2 amin'o -:5 '-.substituted 1,13,4 thiadiazoles may be obtained 1 byucondensing :one

-, equiva-lent of an 'acyl chloride with oneequivalent of thiosem-icarbazide intherpresenceiof one equivalent of a condensing agent of the type illustrated by phosphorus chlorides, such as phosphorus itrichloride, rphosphorus bromides,

.such as phosphorus .oxybromide, andthionyl chlorideren'dering thereaction mixtureialkaline and recovering the '2amino 5-substituted-1,3,4

" thiadiazole from the reactionv mixture. The reaction is exothermim'however, in some instances it'may be desirabletoadd. heat during the course ofthe' reaction and in other'instances it may be-- desirable to apply external coolin to control the reaction within safe'limits. .Theumethod of "thisinvention makes possible substantially improved yields of "2-amino 5-substituted-1,3,4-

thiadiazoles.

*tiibromide; phosphorus. pentabromide and phos- .In a special embodimentof the process lot the .presentiinvention in the preparation of Z-amino- .5+alkenyl-1,3,4-thiadiazoles by this process, one equivalent .of ,achloralkanoyl chloride is con- 5 idensed with one equivalent of thiosemicarbazide ,in .the presencezof .oneequivalent .of a condensing agent selected from those describedin the precedinaparagraph. In the operation of this ,em- .hodiment vof the process, .the *reactantsaare 1 mixed and avarmedto initiate the reaction. The re- ..action as complete when the evolution of 1 hydrogen .chloride 'has ceased. iExternal cooling :may be .rfound necessary to .control the rate of .re-

action. Following this, the .reaction mixture may be processedbyany .desirable procedure for the recovery of the 2-amino-5-alkenyl-1,3,4- thiadiazole. iFor example, the reaction -mixture maybe dissolved in water and hydrolyzed with a1kalifto remove hydrogen chloride from the l2 amino 5 -.chloroalkyl -.1,3,4 thiadiazole hydrochloride. andtoliberate the .free base. i The "free base thereupon precipitated .from the solution onvcooli'ng. may .befiltered off, washed with water-and. dried. I

The followingexamples will serve to illustrate the noveLprocess.oiZ-thepresent invention. These -examples are to .beconstrued merely as illustra- Itiveand not as limiting theinvention except as defined .in theapperidedclaims.

.EXAMPIQEI v '2mmmo-ssemyzsz;s,4=miadiazozeg A mixture of ..9.;2 g. (0.1 :mole) .of propionyl chloride, 9.1 g. (0.1.mole) of thiosemicarbazide and 5.5 g. (0.04 mole) "of phosphorus trichloride was heatedwwith stirringetobO C. .at' which point 7 hydrogen chloride was evolved and the reaction 'adding"50% .sodium hydroxide solution to the cooled solution. "The product, .2-amino-5-e'thyl- 1,3;4'-thiadiazo1e, precipitated from the alkaline solution, was'filteredywashed with water. and

'dfid"at"80 C. Melting point'I88-193 C. Yield,

gpropionylchloride; 39 g. (0.5 mole) of'thiosemiphotus oxybromide. 55 *ca'rbazide' and 27.1 g. (0.13 mole) of phosphorus pentachloride was prepared, heated with stirring to approximately 35 C. and thereafter maintained at a. temperature below 60 C. until the evolution of hydrogen chloride had ceased. Thereafter, the reaction mixture was dissolved in approximately 400 cc. of warm 50% alcohol containing 50 g. of sodium hydroxide. The resulting mixture was refluxed for 3 hours, water was added, alcohol was distilled all and the residual mixture was cooled. The solid product which formed in the solution was filtered off, washed and dried. This material was 2-amino- 5-vinyl-1,3,4-thiadiazole. chloro propionyl chloride, alpha-chloro propionyl chloride may be employed.

EXAMPLE III Z-amino-S -cycZopropyZ-1,3,4-thiadiazole A mixture of 22.9 g. (0.20 mole) of cyclopropyl carbonyl chloride, 18.2 g. (0.20 mole) of thiosemicarbazide and 11.9 g. (0.07 mole) of phosphorus oxychloride was prepared, heated with stirring to 50 C. and maintained at a temperature below 60 C. until the evolution of hydrogen chloride had ceased. Thereafter the reaction mixture was cooled to room temperature, dissolved in 250 cc. of water and filtered. The solution was rendered alkaline by slowly adding 50% sodium hydroxide solution to the cooled solution of reaction products and the material which precipitated in the solution was filtered ofl, washed with water and dried at 80 C. Melting point 210-211 C. (Corr.) Yield 77%.

EXAMPLE IV 2amino-5-benzyZ-1,3,4-thiadiazole A mixture of 0.25 mole of phenylacetyl chloride, 0.25 mole of thiosemicarbazide and 0.10 mole of phosphorus tribromide was prepared and heated with stirring to 40-50" C. to initiate the reaction, as evidenced by the evolution of hydrogen chloride and hydrogen bromide. The reaction temperature was thereafter kept below 60 C. until the evolution of the hydrohalides had ceased. The reaction mixture was thereafter cooled in a water bath to room temperature, dissolved into 200 cc. of water and filtered. The filtrate was made alkaline by slowly adding 50% sodium hydroxide solution to the cooled filtrate. The solid material which precipitated was filtered off, washed with water and dried. The product was 2-amino-5-benzyl-1,3,4-thiadlazole.

EXAMPLE V 2-amino-5-propenyl-1,3,4-thiadiazole .with 50% sodium hydroxide solution. The solid material which separated from the solution was filtered off, washed and dried. The product was 2-amino-5-propenyl-1,3,4-thiadiazole.

EXAMPLE VI Z-amino-5methyl-1,3,4-thiadiazole A mixture of 39.3 g. (0.5 mole) of acetyl chlovride, 45.7. g. (0.5 mole) of thiosemicarbazide and 38 g. (0.28 mole) of sulfur monochlorideKSzCh) In place of beta-- was prepared and warmed with stirring to 350 C. to start the reaction, and the reaction temperature was maintained below 60 C. until the evolution of hydrogen chloride had ceased. Thereafter the reaction mixture was cooled to room temperature, dissolved in 150 cc. of water and filtered. The filtrate was rendered alkaline with 50% sodium hydroxide solution. The solid material which precipitates on cooling the alkaline solution was filtered off, washed and dried. The product was 2-amino-5-methyl-1,3,4-thiadiazole.

EXAMPLE VII Z-amino-5-butyl-1,3,4-thiadiazole A mixture of 36.2 g. (0.3 mole) of valeryl chloride, 27.4 g. (0.3 mole) of thiosemicarbazide and 38.5 g. (0.33 mole) chlorosulfonic acid was prepared and warmed with stirring to 40-50 C. to initiate the reaction, as evidenced by the evolution of hydrogen chloride. The reaction'mixture was kept at a temperature below 60 C. until the evolution of hydrogen chloride had ceased. The reaction mixture was thereafter cooled in a water bath to room temperature, and carefully poured into 300 cc. of cold water. The reaction mixture solution was then cooled and filtered, the filtrate being made alkaline by carefully, with cooling, adding 35 cc. 50% sodium hydroxidesolution. The solid material, which .precipitated from the cooled alkaline solution, was filtered oiT, washed and dried, and was the product 2-amino-5-butyl- 1,3,4-thiadiazole.

EXAMPLE VIII 2-amzno-5-butenyl-1,3,4-thiadiazole A mixture of 27.4 g. (0.3 mole) of thiosemicarbazide, 42.3 g. (0.3 mole) of alpha-chlorovaleryl chloride and 68.7 g. (0.33 mole) thionyl bromide was prepared and warmed with stirring to 50 C. Thereafter, the reaction temperature was kept below 60 C. until the evolution of hydrogen chloride and hydrogen bromide had ceased. The reaction mixture was then cooled and dissolved into 300 cc. of 50% alcohol containing 25 g. sodium hydroxide. The resulting mixture was refluxed for 3 hours, water added, the alcohol distilled ofi, and the residual mixture cooled. The solid product formed was filtered 01f, washed and dried.- The material was 2-amino-5-butenyl-1,3,4-thiadiazole.

EXAMPLE IX 2-amino-5-propyl-1,3,4-thiadiazole A mixture of 26.6 g. (0.25 mole) of butyryl chloride, 22.8 g. (0.25 mole) thiosemicarbazide and 33.6 g. (0.15 mole) of sulfurmonobromide was prepared and warmed to 50C. at which point hydrogen chloride and hydrogen bromide were evolved and the reactionfproceeded exothermically. The reaction temperature wasmaintained below 60 C. When the evolution of the hydrohalides had ceased, the reaction mixture was cooled to room temperature and thereafter dissolved in 50 cc. of water and filtered. The jfiltrate was rendered alkaline by adding 50% sodium hydroxide solution to the coole'dsolution. The product, 2-amino-5-propyl-1,3,4-thiadiazole, was filtered, washed with water and dried at C.

In the practice of the process of the present invention in order to obtain the maximum beneficial result in the increased yield of the desired product, it is necessary to employ at least one equivalent of Queer the described condensing agents for each equivalent of thiosemicarbazide.

More-ever, *it 'is also necessa y in "order women the best wields, to employ equivalent proportions of the acyl chloride and 'thiosemicarba zlde. Variations from these proportions may be practiced; howevnin each instance it has been found that the best yields and the greatest improvements in yield over the "prior art processes are obtained when the aforescribed proportionsare employed. It is furtherconstrued asbeing within the scope of thepresent invention that more than one equivalent of one-of the herein described condensing agents for each mole of thiosemlcarbazide may be employed. However, it has been found that there 'is' no further beneficial resuit to be derived from using more than one {equivalent of the herein described condensing agents 'for each equivalent of 'thiosemicarbaii'de,

iexcept 'forthe use oi a moderate excess over this ratio to compensate for the possible depletionof the condensing agent in side reactions.

been described and illustrated in the foregoing specification and examplea'it is to be observed that the'present invention is not to be construed as being'limited inrespect-to any particular j's'ubstances, proportions, conditions, or combinations except as defined in the claims.

I claim: 7

1. An improved method of making 2-amino-5- substituted-1,3,4-thiadiazoles in which the5- position substituent is a radical "selected from the group consisting of alkyl, alkenyl aralkyl and cycloalkyl radicals comprising condensing one equivalent of an acyl chloride with one'equi'valent'of thiosemicarbazide in the presence of at least one equivalent of at least one condensing agent selected from the group consisting of thionyl chloride, thionyl bromide, sulfur monochloride, ,sulfur monobromide, chlorosulfonic acid, chlorides of phosphorus, and bromides of phosphorus, rendering the mixture alkaline and recovering the 2 amino 5 substituted 1,3,4- thiadiazole from the reaction mixture. I v

2. An improved method of making 2-amino-5- substituted-1,3,4-thiadiazoles in which the 5- position substituent is a radical selected from the group consisting of alkyl, alkenyl, aralkyl, and cycloalkyl radicals comprising condensing one equivalent of an acyl chloride with one equivalent of thiosemicarbazide in the presence of at least one equivalent of phosphorus trichloride, rendering the mixture alkaline and recovering the 2-amino-5-substituted-1,3,4-thiadiazo1e from the reaction mixture.

3. An improved method of making 2-amino-5- substituted-1,3,4-thiadiazoles in which the 5- position substituent is a radical selected from the group consisting of alkyl, alkenyl, aralkyl and cycloalkyl radicals comprising condensing one equivalent of an acyl chloride with one equivalent of thiosemicarbazide in the presence of at least one equivalent of thionyl chloride, rendering the mixture alkaline and recovering the 2-amino-5- substituted-1,3,4-thiadiazole from the reaction mixture.

4. An improved method of making 2-amino-5- substituted-1,3,4-thiadiazoles in which the 5- {ethyl-1,3,4-thiadiaZole "one equivalent-of propionyl chloride'with one equivalent 'of thiosemicarbazide in. the presence pesiuan sutsdnient 'is 'a ra'aicarseieetee from t he group consisting 'bf aikyl, alkenyl, aralk'yl -alnd 'bvcloalkyl radicals comprising-condensing one equivaleiitoi an acyl -chloride with one equivalent of thiosemicarliazid'e in the p're'sence of at least one equivalent of phosphorus oxychloride, "rendering the reacted-"mixture alkaline andrecovering the Z-arnino 5-substituted 1,34= thiadiazole famine reaction mixture.

5. In theprocessof preparing 2-amino-5-s'u'bstitut'ed-i13,4-thiadia2oles in which the 5-positi6n substituent is a radical selected from the group consisting of alkyl, alkenyl, aralkyl and cycloalkyl radicals, the step comprising condensing one equivalento'f an-a'cyl chloride with-one-equi'vclient -'of thiosemicarba'zide in the presence or at least one equivalent of at least one condensing agent selected from the group consisting of thl'o'nyl chloride, thionyl bromide, sulfur-monochloride, sulfur monobromide, chlorosulfoni'c acid, chlorides of phosphorus, and bromides of phosphorus.

6. In the process of preparing 2-a1'nino 5-s1ib- 'stituted jIBA-thiadieizoles in which the 5 position substituent is a radical selected from the group consisting of alkyl,'alkenyl, aralkyl and cycloalkyl radicals, the step comprising condensing one equivalent of an, acyl chloride'with one equivalent of th'iosem'icarbazide in the presence of at least one equivalent of phosphorus-trichloride.

7. In' the process or preparing 2-a'mino- 5-substitute'd-1,3,4-thiadiazoles' in" which the 5'-position substituent-is a radical' selected from the'g'roup consisting ofalkyl, alkenyl,=aralkyl a ndp'y'c'lo- 'alkylradic'als, the step comprising condensing one equivalent of an'acylchloride with one equivfalent of'thiosemicarbazide in the presence of at leastone equivalent of phosphorus oxychloride. 40

-"8 In 'the'process of preparing Z-amino-fi-sub- 'stituted-1,3,4-thiadiazoles in which the "5-position substituent is a'radical selected from the group consisting of alkyl,alkenyljaralkyl' and cycloalkyl radicals, the step comprising condensing one-equivalent of 'an acyl chloride With one equivalent of thiosemicarbazide in the presence of'at least one equivalent of thionyl chloride.

QH-An improved method of 'making-Z-amin'o-S- comprising condensing f at-least one equivalent of at least one condensin'g agent selected from the group-consisting of thionyl chloride, thionyl bromide, sulfur monochloride, sulfur monobromide, chlorosulfonic acid, chlorides of phosphorus, and bromides of phosphorus, rendering the reacted mixture alkaline and recovering the 2-amino-5-ethyl- 1,3,4-thiadiazole from the reaction mixture.

10. In the process of preparing 2-amino-5- ethyl-1,3,4-thiadiazole, the step comprising condensing one equivalent of propionyl chloride with one equivalent of thiosemicarbazide in the presence of at least one equivalent of at least one condensing agent selected from the group consisting of thionyl chloride, thionyl bromide, sulfur monochloride, sulfur monobromide, chlorosulfonic acid, chlorides of phosphorus, and bromides of phosphorus.

11. In the process of preparing 2-amino-5- ethyl-1,3,4-thiadiazole, the step comprising condensing one equivalent of propionyl chloride with one equivalent of thiosemicarbazide in the presence of at least one equivalent of phosphorus trichloride.

- 12. An improved method of making 2-amino- S-alkenyl-1,3,4-thiadiazoles comprising condensing one equivalent of a chloroalkanoyl chloride with one equivalent of thiosemicarbazide in the presence of at least one equivalent of at least one condensing agent selected from the group consisting of thionyl chloride, thionyl bromide, sulfur monochloride, sulfur monobromide, chlorosulfonic acid, and chlorides of phosphorus, and bromides of phosphorus, reacting the resulting 2- amino-5-chloralkyl-1,3,4 thiadiazole hydrochloride with an alkaline hydrolyzing agent until hydrogen chloride has been removed from the compound and the free base has been liberated, and subsequently recovering the 2-amino-5- alkenyl-1,3,4-thiadiazole from the reaction mixture.

13. An improved method of making 2-amino-5- vinyl-1,3,4-thiadiazole comprising condensing one equivalent of beta-chloropropionyl chloride with one equivalent of thiosemicarbazide in the presence of at least one equivalent of at least one condensing agent selected from the group consisting of thionyl chloride, thionyl bromide, sulfur monochloride, sulfur monobrornide, chlorosulfonic acid, chlorides of phosphorus, and bromides of phosphorus, reacting the resulting 2-amino-5- chloroethyl-1,3,4-thiadiazole hydrochloride with a hydrolyzing agent until the hydrogen chloride has been removed and the free base has been liberated, and subsequently recovering the 2-amino-5-vinyl- 1,3,4-thiadiazole from the reaction mixture.

14. An improved method of making Z-aminofi-substituted-1,3,4-thiadiazoles in which the" 5- position substituent is a radical selected from the group consisting of alkyl, alkenyl, aralkyl and cycloalkyl radicals comprising condensing one equivalent of an acyl chloride with one equivalent of thiosemicarbazide in the presence of at least one equivalent of at least one condensing agent selected from the group consisting of thionyl chloride, thionyl bromide, sulfur monochloride, sulfur monobromide, chlorosulfonic acid, chlorides of phosphorus, and bromides of phosphorus, and recovering the 2-amino-5-substituted-1,3,4- thiadiazole from the reaction mixture.

15. An improved method of making Z-amino- 5-substituted-1,3,4-thiadiazoles in which the 5- position substituent is a radical selected from the group consisting of alkyl, alkenyl, aralkyl and cycloalkyl radicals comprising condensing one equivalent of an acyl chloride with one equivalent of thiosemicarbazide in the presence of at least one equivalent of phosphorus trichloride, and recovering the 2-amino-5-substituted-l,3,4-thiadiazole from the reaction mixture.

. 16. An improved method of making 2-aminofi-substituted-1,3,4-thiadiazoles in which the 5- position substituent is a radical selected from the group consisting of alkyl, alkenyl, aralkyl and cycloalkyl radicals comprising condensing one equivalent of an acyl chloride with one equivalent of thiosemicarbazide in the presence of at least one equivalent of thionyl chloride, and recovering the 2-amino-5-substituted-1,3,4-thiadiazole from the reaction mixture.

1'7. An improved method of making 2-amlno- 5-substituted-1,3,4-thiacliazoles in which the 5- position substituent is a radical selected from the group consisting of alkyl, alkenyl, aralkyl and cycloalkyl radicals comprising condensing one equivalent of an acyl chloride with one equivalent of thiosemicarbazide in the presence of at least one equivalent of phosphorus oxychloride, and recovering the 2-amino-5-substituted-1,3,4-thiadiazole from the reaction mixture.

18. In the process of preparing 2-amino-5- ethyl-1,3,4-thiadiazole, the step comprising condensing one equivalent of propionyl chloride with one equivalent of thiosemicarbazide in the presence of at least one equivalent of thionyl chloride.

19. In the process of preparing 2-amino-5- ethyl-1,3,4-thiadiazole, the step comprising con- "densing one equivalent of propionyl chloride with one equivalent of thiosemicarbazide in the presence of at least one equivalent of a phosphorus chloride.

GEORGE W. STEAHLY.

REFERENCES CITED The following references are of record in the file of this patent:

UNITED STATES PATENTS Number Name Date 998,772 Hessenland July 25, 1911 FOREIGN PATENTS Number Country Date 503,700 Great Britain Apr. 12, 1939 OTHER REFERENCES Berichte, vol. 29, pp. 2511-2517 (1896). Chemical Abstracts, vol. 36, 70,094 (1942).

Certificate of Correction Patent'No. 2,497,825 H February 14, 1950 GEORGE W. STEAHLY It is hereby certified that error appears in thefprinted specification of the above numbered patent requiring correction as follows:

Column 4,1ines 1 and 2, for 350 0. read 35 0.;

and that the said Letters Patent should be read with this correction therein that the same may conform to the record of the case in the PatentOflice. A

Signed and sealed this 6th day of June, A. D. 1950.

THOMAS F. MURPHY,

Assistant Commissioner of Patents. 

1. AN IMPROVED METHOD OF MAKING 2-AMINO-5SUBSTITUTED-1,3,4-THIADIAZOLES IN WHICH THE 5POSITION SUBSTITUENT IS A RADICAL SELECTED FROM THE GROUP CONSISTING OF ALKYL, ALKENYL, ARALKYL AND CYCLOALKYL RADICALS COMPRISING CONDENSING ONE EQUIVALENT OF AN ACYL CHLORIDE WITH ONE EQUIVALENT OF THIOSEMICARBAZIDE IN THE PRESENCE OF AT LEAST ONE EQUIVALENT OF AT LEAST ONE CONDENSING AGENT SELECTED FROM THE GROUP CONSISTING OF THIONYL CHLORIDE, THIONYL BROMIDE, SULFUR MONOCHLORIDE, SULFUR MOMOBROMIDE, CHLOROSULFONIC ACID, CHLORIDES OF PHOSPHORUS, AND BROMIDES OF PHOSPHORUS, RENDERING THE MIXTURE ALKALINE AND RECOVERING THE 2 - AMINO - 5 - SUBSTITUTED - 1,3,4THIADIAZOLE FROM THE REACTION MIXTURE. 